Although dopamine (DA) replacement therapy is useful for most of the motor symptoms of Parkinson's disease (PD), some troubling symptoms of the disease are refractory to levodopa therapy and may even worsen with such treatment. These include apathy, depression, memory loss, postural instability and freezing episodes. The data presented here suggest that some of these symptoms may be due to brain norepinephrine (NE) deficiency. Such deficiency is not treatable with levodopa, but may, however, respond to "NE replacement threapy." DL-threo-3,4-dihydroxyphenylserine (DL-threo-DOPS) is a nonphysiological precursor of NE which has been shown to undergo decarboxylation in various mammalian tissues, and to yield NE in a similar way to the formation of DA from levodopa. In preliminary clinical experience DL-threo-DOPS has been shown to improve symptoms of PD which were refractory to levodopa therapy. We are proposing 1) to study the effects of DL-threo-DOPS on DA and NE metabolism in the rat brain and, 2) to evaluate the clinical efficacy of DL-threo-DOPS in the treatment of PD. Results are expected to show the effect of DL-threo-DOPS on NE turnover in the rat brain and the effect of such therapy on the dopaminergic pathway. Clinical studies are expected to show the efficacy of DL-threo-DOPS in the therapy of PD and possible side effects of the drug. If DL-threo-DOPS is proven to be a safe and effective precusor of NE in humans, it may open new approaches for future treatment of several other disorders as well.